title: Quantitative analysis of the CD4 T-cell repertoire specific to therapeutic antibodies in healthy donors.
abstract: Therapeutic antibodies are generally partially to fully humanized, yet they can show unwanted immunogenicity and lead to antibody response and adverse effects when administered to humans. As immunogenicity relies on a T-cell-dependent mechanism, we have evaluated in vitro the size of the preexisting CD4 T-cell repertoire specific to therapeutic antibodies in healthy donors. Specific CD4 T cells of individuals with different HLA-DR allotypes were amplified by in vitro stimulation and quantified. Well-known immunogenic proteins, KLH and a murine antibody, exhibited a strong in vitro T-cell response characterized by a mean of preexisting T cells >1 cell/10(6) cells. In contrast, the preexisting CD4 T-cell repertoires specific to 2 chimeric, 2 humanized, and 2 fully human antibodies remained generally inferior to this value, confirming the role of species-specific sequences in their shaping. Mean values ranged from 0.01 to 0.3 cell/10(6) cells and varied not necessarily in relationship with the humanization level of the therapeutic antibodies. Relationship with their known immunogenicity is discussed. These results contribute to a better understanding and prediction of immunogenicity of therapeutic antibodies in humans.
authors.affiliation: Proteus, Nîmes, France. sdelluc@proteus.fr
authors.forename: Stephanie
authors.initials: S
authors.lastname: Delluc
authors.forename: Gilles
authors.initials: G
authors.lastname: Ravot
authors.forename: Bernard
authors.initials: B
authors.lastname: Maillere
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology*; D000918:Antibody Specificity / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D002460:Cell Line; D005838:Genotype; D006684:HLA-DR Antigens / Q000235:genetics / Q000378:metabolism; D059811:HLA-DRB1 Chains; D006801:Humans; D007166:Immunosuppressive Agents / Q000276:immunology; D014019:Tissue Donors
chemical_list: D000911:Antibodies, Monoclonal; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D007166:Immunosuppressive Agents